Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 68 year old man with prostatic carcinoma and extensive painful osteoblastic metastases was discovered to have hypocalcemia (serum calcium 7.1 mg/dl) without evidence of hypoalbuminemia, renal failure or malabsorption. Baseline studies revealed hypocalciuria (24 hour urine calcium less than 5 mg/day), normal serum phosphate (3.4 mg/dl), low tubular reabsorption of phosphate (68 percent), undetectable serum calcitonin, normal serum 25-hydroxyvitamin D, slightly elevated serum parathyroid hormone level and increased urinary cyclic AMP (8.87 mumol/g creatinine). These studies were compatible with secondary hyperparathyroidism. The intravenous administration of parathyroid extract produced no further change in urinary phosphate but a 25-fold increase in nephrogenous cyclic AMP. Three days administration of intramuscular parathyroid extract slowly and temporarily restored serum calcium to normal levels while increasing urinary cyclic AMP and phosphate. Chemotherapy with cyclophosphamide and 5-fluorouracil rendered the patient free of pain while reducing serum acid and alkaline phosphatase levels and restoring serum total and ionized calcium and urinary cyclic AMP excretion to normal.
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PMID:Hypocalcemia with osteoblastic metastases in patient with prostate carcinoma. A cause of secondary hyperparathyroidism. 724 80

A premenopausal woman with soft tissue metastases from a carcinoma of the breast developed hypercalcemia with hypophosphatemia, reduced tubular reabsorption of phosphate, elevated urinary cyclic AMP levels and normal serum PTH levels was observed. Hormonal therapy with testosterone followed by tamoxifen induced normalization of her serum calcium concomitant with the disappearance of the pleural effusion and reduction in the size of her lung metastases. The correlation between the efficacy of antitumor treatment on pleural effusion, lung metastases, and normalization of serum calcium, as well as the elevated PTH level in the pleural effusion, suggest that this breast carcinoma secreted a PTH-like substance.
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PMID:Hypercalcemia in carcinoma of the breast without evidence of bone destruction: beneficial effect of hormonal therapy. 729 87

We investigated the role of signal transduction systems in the attachment of human uveal melanoma cells to matrix proteins. Ocular melanoma cells established from primary tumours attached rapidly to all substrates examined. Preferred substrates of attachment were collagens type I, III and IV and fibronectin rather than laminin, gelatin, arginine-glycine-aspartine, vitronectin, poly-L-lysine or plastic. All cells showed rapid attachment to the preferred substrates (80% within 10 min). Manipulation of intracellular cyclic AMP or protein kinase C activity had relatively little effect on cell attachment. In contrast, attachment was significantly reduced by manipulating either intracellular calcium or calmodulin. After 15 min at 37 degrees C, the calcium ionophore ionomycin (5 microM) reduced attachment to 25%, and TMB8 (50 microM), which can reduce intracellular calcium, reduced attachment to 60%. The experimental calmodulin antagonist J8 (25 microM), a substituted naphthalene sulphonamide, reduced attachment to 40%. Similarly tamoxifen (25 microM), which has calmodulin antagonist activity in vitro, reduced attachment to 55%. Both J8 and tamoxifen inhibited cell attachment to a wide range of matrix proteins, suggesting that this effect on attachment is not dependent on the presence of specific adhesion receptors. Reduction of ocular melanoma tumour cell/matrix interactions through manipulation of intracellular calcium or calmodulin may therefore merit further investigation as a possible approach to reducing metastatic spread.
Clin Exp Metastasis 1994 Nov
PMID:Investigation of the role of signal transduction in attachment of ocular melanoma cells to matrix proteins: inhibition of attachment by calmodulin antagonists including tamoxifen. 792 90

DN-9693, c-AMP: phosphodiesterase inhibits platelet aggregation induced by metastasizing tumor cells and blood-borne metastases of these tumors. Effects of this drug on pulmonary metastases was studied in wKA rats, which were sc implanted with 4-dimethylaminoazobenzene (DAB) induced KDH-8 tumor cells. KDH-8 cells (10(5)) were sc inoculated on day 0 and excised on day 20. DN-9693 was ip injected at a dose of 150 micrograms twice a day for 7 days pre operatively (-7 - 0) or perioperatively (-3 - +3) or postoperatively (0 - +7). The rats were sacrificed on day 20 after surgery, and lung weight and the number of surface pulmonary nodules were measured. Both were significantly decreased in the group of perioperative and postoperative administration of DN-9693. The survival of these rats were furthermore prolonged when Cyclophosphamide (40 mg/kg) was sc injected 3 days after surgical resection. KDH-8 tumor cells (10(4)) were iv inoculated on day 0, and DN-9693 was ip injected at a dose of 150 micrograms twice a day for 7 days on day 0 approximately 7. Rats were sacrificed on day 20, and same studies as above were done. In this artificial pulmonary metastases, the decrease of the number of lung nodules was observed in WKA rat treated with DN-9693. Platelet aggregation induced by KDH-8 tumor cells was inhibited by ADP inhibitor (apyrase, CP/CPK) and thrombin inhibitor (heparin, MD-805); KDH-8 tumor cells induced platelet aggregation by two different mechanisms: ADP-mediated aggregation and thrombin-mediated aggregation. This platelet aggregation by KDH-8 tumor cells was inhibited by DN-9693 with dose-dependency. DN-9693 had no direct anti-tumor effects either in vivo or in vitro. The results indicates that this drug prevents pulmonary metastases by inhibiting platelet aggregation.
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PMID:[Effects of platelet aggregating inhibitor on pulmonary metastases of tumor cells after surgical resection]. 822 73

Until recently, the signal transduction pathways involved in the processes of tumor growth have been poorly understood. In the present study, we investigated cell surface receptors which utilize phosphatidylinositol (Pl) turnover/Ca2+ mobilization as a signal transduction pathway to regulate cell growth in a metastatic human lung carcinoma cell line, PG. We found that purinoceptor agonists, including ATP and its analogs, and bombesin, an amphibian tetradeca-peptide of mammalian homology gastrin-releasing peptide, induced rapid transient increase of cytoplasmic-free Ca2+ in PG cells loaded with fura-2. The Ca2+ responses were derived both from release from internal stores and the opening of plasma membrane Ca2+ channels. HPLC analysis of inositol 1,4,5-triphosphate (Ins(1,4,5)P3) and its isomers showed a receptor-linked phospholipase C activation by ATP and bombesin. Although ATP and bombesin were both able to induce Pl turnover and Ca2+ mobilization in PG cells, they had differential growth regulatory effects on PG cells. Treatment with bombesin stimulated PG cell growth while treatment with ATP inhibited significantly PG cell growth. Pharmacological studies showed that the purinoceptors on PG cells were of the P2 subtype. Other hydrolysis-resistant P2 purinoceptor agonists, including ATP gamma S and AMP-PNP, were as effective as ATP in stimulating Pl turnover and Ca2+ mobilization as well as in inhibiting PG cell growth in vitro, suggesting the potential usefulness of such ATP analogs in clinical trials. Preliminary results suggest G protein involvement in the differential regulation of ATP and bombesin signal transduction pathways.
Clin Exp Metastasis 1993 Jul
PMID:Differential growth regulation of a metastatic human lung carcinoma cell line through activation of phosphatidyl inositol turnover signal transduction pathway. 831 79

In two separate cohorts of breast cancer patients presenting without evidence of distant metastatic disease, high levels of tumour cyclic AMP binding proteins (> 8 pmol/mg cytosol protein) have been shown to be associated with poor prognosis in terms of both disease recurrence and overall survival. This association is independent of known established prognostic factors and allows the identification of a small subgroup of patients whose outlook warrants the implementation of aggressive systemic therapy.
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PMID:Tumour cyclic AMP binding proteins: an independent prognostic factor for disease recurrence and survival in breast cancer. 840 Mar 27

Regulation of two genes involved in tumor invasion, the matrix metalloproteinase (MMP)-1 and the tissue inhibitor of MMP (TIMP)-1, by activators of protein kinase C (PKC) or protein kinase A (PKA) was studied in MCF-7 mammary adenocarcinoma cells. The basal mRNA expression was undetectable for MMP-1 and low for TIMP-1. Treatment of MCF-7 cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (100 nM) was associated with a high expression of MMP-1 mRNA, as well as an induction of the level of TIMP-1 mRNA (5- to 10-fold). In the presence of actinomycin D (AMD, 4.0 microM), an inhibitor of transcription, these stimulatory effects of TPA were abolished. Similar responses were observed when protein synthesis was inhibited by cycloheximide (CHX, 50 microM). In the presence of the cyclic AMP (cAMP) analogue N6-benzoyl (N6-Bzl)-cAMP (500 microM), the MMP-1 mRNA was unaffected and still below the level of detection, whereas a non-significant increase (< 2-fold) in TIMP-1 mRNA was observed. The level of pS2 mRNA, of which the induction by TPA in MCF-7 cells is a primary transcriptional event, was up-regulated (10- to 15-fold) by TPA (100 nM), whereas a much weaker increase (2- to 3-fold) was observed by treatment with N6-Bzl-cAMP (500 microM). Again, these stimulatory effects were counteracted by AMD (4.0 microM) and CHX (50 microM). These data suggest that activation of PKC but not of PKA may induce transcription of MMP-1 and TIMP-1, possibly by the synthesis of transcription factor(s), in transformed cells of epithelial origin.
Clin Exp Metastasis 1996 Sep
PMID:Regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in MCF-7 cells: comparison with regulatory mechanisms of pS2 expression. 887 12

Recently, we reported that low (PC-1)- and high-invasive cell lines (PC-1.0) were established on the basis of hamster pancreatic ductal adenocarcinomas, and PC-1.0 cells were secreting the dissociation factor in the supernatant (DF-CM) which induced cell dissociation and enhancement of cell motility. The cell motility of PC-1.0 is about 6 times as high as that of PC-1, which was continuously maintained in an autocrine fashion by DF-CM. In contrast, cell motility of PC-1 was rapidly induced by DF-CM with a high level of induction of endogenous c-fos mRNA and returned to a basal level within 6 h. The inhibition experiment using antisense oligonucleotides to c-fos indicated that the high level of induction of c-fos mRNA observed in the DF-CM-treated PC-1 cells was closely associated with their induction of cell motility. To elucidate these differences of responses against DF-CM between PC-1 and PC-1.0, signal transduction pathways of induction of the cell motilities were analyzed, using protein kinase C (PKC) inhibitor, 12-O-tetradecanoylphorbol-13-acetate, cyclic AMP antagonist, and cyclic AMP agonist. The transiently enhanced cell motility of DF-CM-treated PC-1 cells was completely inhibited by the cyclic AMP antagonist, and the cyclic AMP agonist was able to induce a similar pattern of induction of cell motility in PC-1 cells to DF-CM. On the other hand, the highly enhanced cell motility of PC-1.0 was completely inhibited by protein kinase C inhibitor, but not by cyclic AMP antagonist. These results suggest that cell motility of low-invasive PC-1 cells is under control through cyclic AMP-dependent protein kinase A, while the protein kinase C pathway seems favorable for high-invasive PC-1.0 cells to maintain the continuously enhanced cell motility responsible for their high invasiveness.
Invasion Metastasis 1997
PMID:Signal transduction pathway of the induction of cell motility in hamster pancreatic ductal adenocarcinoma cell. 942 21

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.
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PMID:Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. 1536 99

The tumor metastasis suppressor gene Drg-1 has been shown to suppress metastasis without affecting tumorigenicity in immunodeficient mouse models of prostate and colon cancer. Expression of Drg-1 has also been found to have a significant inverse correlation with metastasis or invasiveness in various types of human cancer. However, how Drg-1 exerts its metastasis suppressor function remains unknown. In the present study, to elucidate the mechanism of action of the Drg-1 gene, we did a microarray analysis and found that induction of Drg-1 significantly inhibited the expression of activating transcription factor (ATF) 3, a member of the ATF/cyclic AMP-responsive element binding protein family of transcription factors. We also showed that Drg-1 attenuated the endogenous level of ATF3 mRNA and protein in prostate cancer cells, whereas Drg-1 small interfering RNA up-regulated the ATF3 expression. Furthermore, Drg-1 suppressed the promoter activity of the ATF3 gene, indicating that Drg-1 regulates ATF3 expression at the transcriptional level. Our immunohistochemical analysis on prostate cancer specimens revealed that nuclear expression of ATF3 was inversely correlated to Drg-1 expression and positively correlated to metastases. Consistently, we have found that ATF3 overexpression promoted invasiveness of prostate tumor cells in vitro, whereas Drg-1 suppressed the invasive ability of these cells. More importantly, overexpression of ATF3 in prostate cancer cells significantly enhanced spontaneous lung metastasis of these cells without affecting primary tumorigenicity in a severe combined immunodeficient mouse model. Taken together, our results strongly suggest that Drg-1 suppresses metastasis of prostate tumor cells, at least in part, by inhibiting the invasive ability of the cells via down-regulation of the expression of the ATF3 gene.
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PMID:The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer. 1717 97


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